NF-κB activation in endothelial cells is critical for the activity of angiostatic agents

Sebastien P. Tabruyn, Sylvie Mémet, Patrick Avé, Catherine Verhaeghe, Kevin H. Mayo, Ingrid Struman, Joseph A. Martial, Arjan W. Griffioen

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

In tumor cells, the transcription factor NF-κB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth factor. Fromth ese data, a protumorigenic role of NF-κB has emerged. Here, we examined in endothelial cells whether NF-κB signaling pathway is involved in mediating the angiostatic properties of angiogenesis inhibitors. The current report describes that biochemically unrelated agents with direct angiostatic effect induced NF-κB activation in endothelial cells. Our data showed that endostatin, anginex, angiostatin, and the 16-kDa N-terminal fragment of human prolactin induced NF-κB activation in endothelial cells in both cultured human endothelial cells and in vivo in a mouse tumor model. It was also found that NF-κB activity was required for the angiostatic activity, because inhibition of NF-κB in endothelial cells impaired the ability of angiostatic agents to block sprouting of endothelial cells and to overcome endothelial cell anergy. Therefore, activation of NF-κB in endothelial cells can result in an unexpected antitumor outcome. Based on these data, the current approach of systemic treatment with NF-κB inhibitors may therefore be revisited because NF-κB activation specifically targeted to endothelial cells might represent an efficient strategy for the treatment of cancer.

Original languageEnglish (US)
Pages (from-to)2645-2654
Number of pages10
JournalMolecular Cancer Therapeutics
Volume8
Issue number9
DOIs
StatePublished - Sep 1 2009

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